Complementary Control of Sensory Adaptation by Two Types of Cortical Interneurons

Reliably detecting unexpected sounds is important for environmental awareness and survival. By selectively reducing responses to frequently, but not rarely, occurring sounds, auditory cortical neurons are thought to enhance the brain\u27s ability to detect unexpected events through stimulus-specific adaptation (SSA). The majority of neurons in the primary auditory cortex exhibit SSA, yet little is known about the underlying cortical circuits. We found that two types of cortical interneurons differentially amplify SSA in putative excitatory neurons. Parvalbumin-positive interneurons (PVs) amplify SSA by providing non-specific inhibition: optogenetic suppression of PVs led to an equal increase in responses to frequent and rare tones. In contrast, somatostatin-positive interneurons (SOMs) selectively reduce excitatory responses to frequent tones: suppression of SOMs led to an increase in responses to frequent, but not to rare tones. A mutually coupled excitatory-inhibitory network model accounts for distinct mechanisms by which cortical inhibitory neurons enhance the brain\u27s sensitivity to unexpected sounds

Male Oxidative Stress Infertility (MOSI): Proposed Terminology and Clinical Practice Guidelines for Management of Idiopathic Male Infertility

Despite advances in the field of male reproductive health, idiopathic male infertility, in which a man has altered semen characteristics without an identifiable cause and there is no female factor infertility, remains a challenging condition to diagnose and manage. Increasing evidence suggests that oxidative stress (OS) plays an independent role in the etiology of male infertility, with 30% to 80% of infertile men having elevated seminal reactive oxygen species levels. OS can negatively affect fertility via a number of pathways, including interference with capacitation and possible damage to sperm membrane and DNA, which may impair the sperm’s potential to fertilize an egg and develop into a healthy embryo. Adequate evaluation of male reproductive potential should therefore include an assessment of sperm OS. We propose the term Male Oxidative Stress Infertility, or MOSI, as a novel descriptor for infertile men with abnormal semen characteristics and OS, including many patients who were previously classified as having idiopathic male infertility. Oxidation-reduction potential (ORP) can be a useful clinical biomarker for the classification of MOSI, as it takes into account the levels of both oxidants and reductants (antioxidants). Current treatment protocols for OS, including the use of antioxidants, are not evidence-based and have the potential for complications and increased healthcare-related expenditures. Utilizing an easy, reproducible, and cost-effective test to measure ORP may provide a more targeted, reliable approach for administering antioxidant therapy while minimizing the risk of antioxidant overdose. With the increasing awareness and understanding of MOSI as a distinct male infertility diagnosis, future research endeavors can facilitate the development of evidence-based treatments that target its underlying cause

Cortical Interneurons Differentially Shape Frequency Tuning following Adaptation

Summary: Neuronal stimulus selectivity is shaped by feedforward and recurrent excitatory-inhibitory interactions. In the auditory cortex (AC), parvalbumin- (PV) and somatostatin-positive (SOM) inhibitory interneurons differentially modulate frequency-dependent responses of excitatory neurons. Responsiveness of neurons in the AC to sound is also dependent on stimulus history. We found that the inhibitory effects of SOMs and PVs diverged as a function of adaptation to temporal repetition of tones. Prior to adaptation, suppressing either SOM or PV inhibition drove both increases and decreases in excitatory spiking activity. After adaptation, suppressing SOM activity caused predominantly disinhibitory effects, whereas suppressing PV activity still evoked bi-directional changes. SOM, but not PV-driven inhibition, dynamically modulated frequency tuning with adaptation. Unlike PV-driven inhibition, SOM-driven inhibition elicited gain-like increases in frequency tuning reflective of adaptation. Our findings suggest that distinct cortical interneurons differentially shape tuning to sensory stimuli across the neuronal receptive field, altering frequency selectivity of excitatory neurons during adaptation. : Natan et al. describe how a specific component in the neural circuitry in a key auditory part of the brain helps the auditory system tease apart complex sounds. This happens through adaptation of neuronal responses to temporally repeated sounds. Keywords: auditory cortex, interneurons, cortical processing, inhibition, adaptation, frequency tuning, auditory processing, optogenetics, archaerhodopsi

Differential Short-Term Plasticity of PV and SST Neurons Accounts for Adaptation and Facilitation of Cortical Neurons to Auditory Tones

Cortical responses to sensory stimuli are strongly modulated by temporal context. One of the best studied examples of such modulation is sensory adaptation. We first show that in response to repeated tones pyramidal (Pyr) neurons in male mouse auditory cortex (A1) exhibit facilitating and stable responses, in addition to adapting responses. To examine the potential mechanisms underlying these distinct temporal profiles, we developed a reduced spiking model of sensory cortical circuits that incorporated the signature short-term synaptic plasticity (STP) profiles of the inhibitory parvalbumin (PV) and somatostatin (SST) interneurons. The model accounted for all three temporal response profiles as the result of dynamic changes in excitatory/inhibitory balance produced by STP, primarily through shifts in the relative latency of Pyr and inhibitory neurons. Transition between the three response profiles was possible by changing the strength of the inhibitory PV→Pyr and SST→Pyr synapses. The model predicted that a unit's latency would be related to its temporal profile. Consistent with this prediction, the latency of stable units was significantly shorter than that of adapting and facilitating units. Furthermore, because of the history-dependence of STP the model generated a paradoxical prediction: that inactivation of inhibitory neurons during one tone would decrease the response of A1 neurons to a subsequent tone. Indeed, we observed that optogenetic inactivation of PV neurons during one tone counterintuitively decreased the spiking of Pyr neurons to a subsequent tone 400 ms later. These results provide evidence that STP is critical to temporal context-dependent responses in the sensory cortex.SIGNIFICANCE STATEMENT Our perception of speech and music depends strongly on temporal context, i.e., the significance of a stimulus depends on the preceding stimuli. Complementary neural mechanisms are needed to sometimes ignore repetitive stimuli (e.g., the tic of a clock) or detect meaningful repetition (e.g., consecutive tones in Morse code). We modeled a neural circuit that accounts for diverse experimentally-observed response profiles in auditory cortex (A1) neurons, based on known forms of short-term synaptic plasticity (STP). Whether the simulated circuit reduced, maintained, or enhanced its response to repeated tones depended on the relative dominance of two different types of inhibitory cells. The model made novel predictions that were experimentally validated. Results define an important role for STP in temporal context-dependent perception

In vivo volumetric imaging of calcium and glutamate activity at synapses with high spatiotemporal resolution.

Studying neuronal activity at synapses requires high spatiotemporal resolution. For high spatial resolution in vivo imaging at depth, adaptive optics (AO) is required to correct sample-induced aberrations. To improve temporal resolution, Bessel focus has been combined with two-photon fluorescence microscopy (2PFM) for fast volumetric imaging at subcellular lateral resolution. To achieve both high-spatial and high-temporal resolution at depth, we develop an efficient AO method that corrects the distorted wavefront of Bessel focus at the objective focal plane and recovers diffraction-limited imaging performance. Applying AO Bessel focus scanning 2PFM to volumetric imaging of zebrafish larval and mouse brains down to 500 µm depth, we demonstrate substantial improvements in the sensitivity and resolution of structural and functional measurements of synapses in vivo. This enables volumetric measurements of synaptic calcium and glutamate activity at high accuracy, including the simultaneous recording of glutamate activity of apical and basal dendritic spines in the mouse cortex

Activating PVs increases tone-evoked responses, whereas suppressing PVs has the opposite effect.

<p>A, C, E. Scaled time course of the firing rate of the neurons in response to a tone (outlined by black dashed lines) on light-On (color) and light-Off (gray) trials. Time of laser onset and offset is outlines by vertical color dashed lines. Mean ± SEM. A. PV-ChR2 mice. C. PV-Arch mice. E. CamKIIα-ChR2 mice. Inset diagram shows circuits targeted by photomodulation. B, D, F. Left. Scaled responses to tones on light-On trials plotted against responses on light-Off trials for putative excitatory neurons. Response magnitude is defined as a difference in mean scaled FR_base (0–50 ms before tone onset) and mean response to tone (FR_tone, 0–50 ms after tone onset). Right. Mean ± SEM. responses to tones from the left panel. See data in <a href="http://www.plosbiology.org/article/info:doi/10.1371/journal.pbio.1002308#pbio.1002308.s001" target="_blank">S1 Data</a>. B. PV-ChR2 mice: Tone-evoked responses on light-On trials (blue) were significantly higher than on light-Off trials (gray). Paired <i>t</i> test, <i>n</i> = 550, <i>t</i>₅₄₉ = 5.81, <i>p</i> = 1.1e-8. Data are combined for three laser powers used to activate PV interneurons (0.2, 0.5, and 10 mW/mm²). D. PV-Arch mice: Tone-evoked responses on light-On trials (green) were significantly lower than on light-Off trials (gray). Paired <i>t</i> test, <i>n</i> = 127, <i>t</i>₁₂₆ = 6.70, <i>p</i> = 6.3e-10. F. CamKIIα-ChR2 mice: Tone-evoked responses were not significantly affected by light. Paired <i>t</i> test, <i>n</i> = 130, <i>t</i>₁₂₉ = 1.19, <i>p</i> = 0.22. G. Change in the magnitude of scaled response to tones is correlated with change in behavioral <i>Th</i> due to manipulation of PVs activity. Each dot represents data averaged for single units from each subject at one light intensity (only subjects with >5 identified single units were included). Blue: PV-ChR2 group (<i>n</i> = 28); Green: PV-Arch group (<i>n</i> = 5). Magenta: CamkIIα-ChR2 group (<i>n</i> = 6, not included in regression analysis). <i>p</i> = 0.01.</p

PV neurons control learned frequency specificity.

<p>A. Diagram of DAFC and testing protocols. During DAFC, both CS+ and CS− overlapped with photostimulation of the AC by blue (PV-ChR2 group) or green light (PV-Arch group). During the test session 24 h later, tones at 4 frequencies were presented without US and photostimulation. B. Results of the test for LS in PV-ChR2 (left, <i>n</i> = 13) and PV-Arch (right, <i>n</i> = 15). PV-Arch group (green) showed no significant decline in freezing to test tones (repeated measures ANOVA, <i>F</i>_3,42 = 0.92, <i>p</i> = 0.44), whereas PV-ChR2 group (blue) and control group (gray, <i>n</i> = 8) showed significant decline in freezing (<i>F</i>_3,36 = 15.5, <i>p</i> < 0.0001; <i>F</i>_3,21 = 4.17, <i>p</i> = 0.018 respectively). Mean ± SEM. Arrows depict frequencies used as CS− and CS+ during conditioning. C. LS test for CamKIIα-ChR2 (<i>n</i> = 6, magenta) and control group (<i>n</i> = 8, gray). Mean ± SEM. CamKIIα-ChR2 mice showed significant decline in freezing (repeated measures ANOVA <i>F</i>_3,15 = 5.83, <i>p</i> = 0.008). Arrows depict frequencies used as CS− and CS+ during conditioning. D. Average LS index (LS) for mice in PV-Arch group (green bar) was significantly lower than LS for mice in the control group injected with a control viral construct (gray bar, <i>t</i> test with Bonferroni adjustment, <i>t</i>₁₉ = 3.28, <i>p</i> = 0.012). Mean LS for PV-ChR2 (blue) and CamKIIα-ChR2 group (magenta) were not significantly different from LS for control mice. ns: <i>t</i> test, t₂₁ = 0.1, <i>p</i> = 0.92 and <i>t</i>₁₂ = 1.14, <i>p</i> = 0.28 respectively. Dots depict data for an individual subject. Bars depict mean value for each group. E. Specificity of the freezing response versus index of change in <i>Th</i> due to photostimulation of PV activity. Each circle depicts a single mouse. Green: PV-Arch group (<i>n</i> = 13 mice). Blue: PV-ChR2 group (<i>n</i> = 15). Pearson = 0.59, R² = 0.35, <i>p</i> = 0.0009. CamKIIα-ChR2 group (<i>n</i> = 6) is shown in magenta but not included in statistical analysis. See data in <a href="http://www.plosbiology.org/article/info:doi/10.1371/journal.pbio.1002308#pbio.1002308.s001" target="_blank">S1 Data</a>. F. Specificity of freezing responses (left) but not sparseness (right) significantly correlated with the change in the magnitude of tone-evoked responses. Green: PV-Arch group (<i>n</i> = 5). Blue: PV-ChR2 group (<i>n</i> = 5). Magenta: CamKIIα-ChR2 group (<i>n</i> = 6) is not included in correlation analysis. See data in <a href="http://www.plosbiology.org/article/info:doi/10.1371/journal.pbio.1002308#pbio.1002308.s001" target="_blank">S1 Data</a>.</p

Optogenetic silencing or activation of neuronal activity.

<p>A, F, K. PV-Cre mice were injected bilaterally with either AAV-FLEX-ChR2-tdTomato (A) or AAV-FLEX-Arch-GFP (F). CamKIIα-Cre mice (K) were injected with AAV-FLEX-ChR2-tdTomato. All animals were implanted with optical fibers bilaterally targeting AC and neuronal activity was recorded using a multichannel silicon probe in AC (left panel). Schematic of the circuits targeted by photomodulation (right panel). PV-ChR2 group: Blue light (473 nm) activates PVs, thereby inhibiting excitatory neurons in mice expressing ChR2 in PVs. PV-Arch group: Green light (532 nm) suppresses PVs, thereby activating excitatory neurons in mice expressing Arch in PVs. CamKIIα-ChR2 group: Blue light directly activates excitatory neurons in mice expressing ChR2 in excitatory neurons. B, G, L. Specificity (Sp) and effectiveness (E) of viral expression in PV-ChR2 group (B, <i>n</i> = 4 mice), PV-Arch group (G, <i>n</i> = 3), and CamKIIα-ChR2 group (L, <i>n</i> = 2). Bars represent mean ± SEM (standard error of the mean). C, H, M. Immunohistochemistry demonstrating coexpression of the virus with the respective cell type in AC. A.: Channelrhodopsin-tdTomato (ChR2-tdTomato) expressed in PV-Cre mouse AC. Red: tdTomato. Green: antibody for parvalbumin. H.: Archaerhodopsin-GFP (Arch-GFP) expressed in PV-Cre mouse AC. Green: GFP. Red: antibody for parvalbumin. M.: ChR2-tdTomato expressed in CamKIIα-Cre mouse AC. Red: tdTomato. Green: antibody for CamKIIα. Scale bar, 50 μm. D, I, N. Responses of neurons to optogenetic stimulation. Light was presented from 0 to 0.25 s (color rectangle). Top: Raster plot of spike times of a representative neuron activated by photostimulation from each of PV-ChR2 (D), PV-Arch (I), and CamKIIα-ChR2 (N) group. Bottom. Corresponding peristimulus time histogram (PSTH) of neuronal response in light-On (color) and light-Off (gray) conditions. E, J. Optogenetic activation of PVs in PV-ChR2 group (E) suppressed spontaneous firing rate (FR_base), whereas suppression of PVs in PV-Arch mice (J) increased FR_base of neurons recorded from AC. Bottom: Scatter plot of spontaneous firing rate on light-On plotted versus light-Off trials. Each circle represents a single unit. Closed and open circles represent significant and nonsignificant effect of light respectively (paired <i>t</i> test, comparing FR 50 ms before and after light onset). Top: Histograms of index of change in FR_base due to photoactivation (E) and photosuppression (J) of PVs over the neuronal population. Arrowhead: mean. (PV-ChR2: ΔFR_base = −0.13; PV-Arch: ΔFR_base = 0.12); ***: <i>p</i> < 0.001 (one-sample <i>t</i> test; PV-ChR2: <i>n</i> = 330, <i>t</i>₃₂₉ = 11.2, <i>p</i> = 7.4e-25; PV-Arch: <i>n</i> = 212, <i>t</i>₂₁₁ = 11.8, <i>p</i> = 4.9e-25). See data in <a href="http://www.plosbiology.org/article/info:doi/10.1371/journal.pbio.1002308#pbio.1002308.s001" target="_blank">S1 Data</a>. O. Direct photoactivation of CamKIIα neurons leads to a significant increase in FR_base. Top: index of change in the FR_base across neuronal population. Bottom: FR_base in light-On trials versus light-Off trials. ***: one-sample <i>t</i> test, <i>n</i> = 206, t₂₀₅ = 11.84, <i>p</i> = 5.4e-25, mean ΔFR_base = 0.27. See data in <a href="http://www.plosbiology.org/article/info:doi/10.1371/journal.pbio.1002308#pbio.1002308.s001" target="_blank">S1 Data</a>.</p